Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide.
ABSTRACT The inhibitory effect of Andrographis paniculata extract (APE) and andrographolide (AND), the most medicinally active phytochemical in the extract, on hepatic cytochrome P450s (CYPs) activities was examined using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-O-deethylation, CYP2B1-dependent benzyloxyresorufin-O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation and CYP3A-dependent testosterone 6 beta-hydroxylation activities, were determined in the presence and absence of APE or AND (0-200 microM). APE inhibited ethoxyresorufin-O-deethylation activity in rat and human liver microsomes, with apparent Ki values of 8.85 and 24.46 microM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent Ki values of 8.21 and 7.51 microM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with Ki of 25.43 microM. AND was found to be a weak inhibitor of rat CYP2E1 with a Ki of 61.1 microM but did not affect human CYP2E1. In conclusion, it cannot be excluded from the present study that APE could cause drug-drug interactions in humans through CYP3A and 2C9 inhibition.
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ABSTRACT: The present investigation addresses the inhibitory potential of five Andrographis paniculata (AP) extracts of different polarity and its three active constituents on UGT1A1, UGT1A4 and UGT2B7. Bioluminescent assay with luciferin as a substrate was used to determine IC50 values for all extracts and constituents. The kinetic enzyme inhibition experiments were subsequently performed to determine Ki values and inhibition modes for extracts and constituents having IC50 values less than 10 μg/mL. Our results in general exhibit that AP extracts and constituents potently inhibited UGT1A1 and UGT2B7 with varying degrees of inhibition featuring Ki values from 1.0 up to 7.5 μg/mL. On the other hand, none of them showed significant inhibitory effect on UGT1A4. Of the extracts tested, AP ethanolic, AP aqueous (root) and AP aqueous (leaf) were found to inhibit UGT1A1, while the remaining, were devoid of any potent interaction. In contrast, AP ethanolic was found to exclusively and competitively inhibit UGT2B7. Of the constituents examined, andrographolide and 14-Deoxy-11,12-didehydroandrographolide were found to inhibit the activity of UGT2B7, while neoandrographolide and 14-Deoxy-11,12-didehydroandrographolide inhibited UGT1A1, partially implying their relative content in the extracts, consequently representing correlation with inhibition seen in the corresponding extracts. These findings suggest that AP extracts could cause herb-drug interactions via inhibition of UGT isoforms. An in vivo study is needed to examine this further.International Journal of Pharmacy and Pharmaceutical Sciences 03/2014; 6(6):58-66. · 1.59 Impact Factor
- Chinese Medicine 01/2012; 03(03):136-143. DOI:10.4236/cm.2012.33022
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ABSTRACT: Ethnopharmacological relevance: Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. Material and methods: Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat. Results: SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5 g/kg, qd x 7d) and alcoholic extract (1.5 g/kg, qd x 7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and gamma-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated C-max (10 fold). Conclusion: These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.Journal of Ethnopharmacology 08/2014; 155(3). DOI:10.1016/j.jep.2014.07.026 · 2.94 Impact Factor